This project includes studies in vitro and in vivo in rodents, in non-human primates, and in humans. The monoaminergic neurotoxic properties of a variety of amphetamine analogs, including (?) 3,4-methylenedioxymethamphetamine, fenfluramine, methcathinone, and methamphetamine are first determined in vitro and in animals, and the utility of various biological assays for the detection of neurotoxicity are determined. Methods include cerebrospinal fluid assay of monoamine metabolites, direct neurochemical assessment of monoamines and their metabolites, their synthetic enzymes, and their transporters. When indicated, neuroanatomical studies using immunohistofluorescent techniques are performed. Further, a recently developed positron emission tomography (PET) ligand [11-C]McN5652 is used to determine whether exposure to amphetamine analogs is associated with a reduction in [11-C]McN5652-labeled 5-HT transporters. PET studies are initially conducted in non-human primates and, when appropriate, are than conducted in humans. Similarly, when one of the various amphetamine analogs is determined to be neurotoxic to dopamine neurons in animals, PET studies are first conducted in baboons using [11-C]WIN-35,428, a PET ligand that selectively labels the dopamine transporter. If indicated, studies are then conducted in humans. Finally, in addition to assessment of the neurotoxic potential of various amphetamine analogs, efforts are being made to determine the functional consequences of amphetamine-induced neurotoxic injury, if it exists. To this end, non-human primates and humans undergo batteries of behavioral tests to evaluate functional spheres thought to be modulated by monoamines. In humans, these batteries include cognitive testing, sleep studies, neuroendocrine studies, personality evaluation, neuropsychiatric testing, and pain testing.